Publicações associadas

Mutarotation of aldoses: Getting a deeper knowledge of a classic equilibrium enabled by computational analyses

The mutarotation equilibrium, by which reducing carbohydrates exist in solution as the α and β anomers of cyclic (furanoid and pyranoid) structures, along with open-chain (aldehyde and hydrate) forms, and whose ratios are depending on factors such as temperature, pH and solvent, portraits a phenomenon involved in numerous processes of chemical and biological importance. Herein, we have developed a DFT-based rationale that provides a broader landscape for anomerizations and ring-open chain interconversions, together with the pivotal role exerted not only by the aldehyde intermediate (essentially the only acyclic structure taken into account so far), but also the hydrate form (often more abundant at the equilibrium). These calculations reveal a more complex and richer scenario than was thought, and identify different mutarotation mechanisms that hinge on every monosaccharide. It is noteworthy that pyranose-furanose interconversion may actually occur without the intermediacy of open-chain forms. For the aldoses evaluated, namely d-glucose, d-ribose, and d-xylose, all structures involved in mutarotation undergo interconversion pathways, whose energy barriers calculated at the M06-2X/6-311++G(d,p) level, are in good agreement with previous experimental measurements.

Fuente de la publicación: 
  • Juan García de la Concepción, R. Fernando Martínez, Pedro Cintas, Reyes Babiano. Mutarotation of aldoses: Getting a deeper knowledge of a classic equilibrium enabled by computational analyses. Carbohydrate Research, Volume 490, 2020. doi: 10.1016/j.carres.2020.107964

Assessing Oxygen Vacancies in Bismuth Oxide through EELS Measurements and DFT Simulations

Pioneering electron energy loss spectroscopy (EELS) measurements of α-Bi2O3 are performed on three samples obtained through different synthesis methods. Experimental low-loss and core-loss EELS spectra are acquired. By combining them with detailed structural characterization and Density Functional Theory (DFT) simulations, we are able to detect and evaluate the presence of oxygen vacancies in the samples. This type of information has not been accessed previously from EELS data in bismuth oxide, because high-resolution EELS spectra or how vacancies reflect in Bi2O3 spectra were unreported. This novel measurement is further validated through comparison with photoluminescence data. Therefore, the technique has the ability to probe oxygen vacancies in Bi2O3 at an unprecedented resolution, which might allow solving material science and technological issues related to this material.

Fuente de la publicación: 
  • Assessing Oxygen Vacancies in Bismuth Oxide through EELS Measurements and DFT Simulations.
    Pau Torruella, Catalina Coll, Gemma Martín, Lluís López-Conesa, María Vila, Carlos Díaz-Guerra, María Varela, María Luisa Ruiz-González, Javier Piqueras, Francesca Peiró, and Sònia Estradé.
    The Journal of Physical Chemistry C 2017 121 (44), 24809-24815.
    DOI: 10.1021/acs.jpcc.7b06310.

Computational insights into cycloadditions of thioisomünchnones with acetylenes: how does sulfur escape from cycloadducts?

The spontaneous loss of sulfur or isocyanate from transient 7-thia-2-azabicyclo[2.2.1]hept-5-en-3-ones, which are initially formed by 1,3-dipolar cycloadditions of thioisomünchnones with acetylenic dipolarophiles, is the key step in the chemoselective syntheses of pyridin-2-ones or thiophenes. The way by which sulfur is released has been the subject of previous studies pointing to a concerted retro-cheletropic mechanism as a more favorable route than the alternative stepwise pathway. The latter however, is apparently prevalent for elimination of isocyanate. Working with a conformationally-restricted bicyclic thioisomünchnone that undergoes facile cycloaddition with acetylenes, sulfur elimination has now been interrogated by experiment and theoretical calculations at the M06-2X and M11 methods in combination with the 6-311++G(d,p) basis set, which unveil rather a sigmatropic shift via the intermediacy of thiirane species. These results provide new vistas and synthetic opportunities in mesoionic cycloadditions.

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Assessing stereoelectronic effects in dipolar cycloadditions yielding fused thiazolopyridone rings

Here is reported a combined experimental and computational study on the cycloadditions of bicyclic 1,3-thiazolium-4-olates, derived from thiazolidin-2-thiones, with asymmetrically-substituted acetylenes. These results provide further mechanistic insights into the above dipolar cycloadditions and enable an unequivocal characterization by NMR spectroscopy of regiochemical patterns as previous derivatives had substituents at both C-2 (in the dipole) and C-6 (in products). Accordingly, new dihydrothiazolopyrid-2-ones have been obtained from a thioisomünchnone lacking substitution at C-2. With the aim of assessing the steric hindrance as well as the facial stereoselection induced by a bulky group on the Si face (relative to C-7a) of the mesoionic heterocycle, a chiral thioisomünchnone has also been obtained along with the resulting optically active thiazolopyridones. A computational study of these particular cycloadditions, largely based on a natural bond orbital (NBO) analysis, allowed us to evaluate the influence of substituents on intermolecular steric repulsions, charge transfers, as well as solvent effects.

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An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs

Marine secondary metabolites are a promising source of unexploited drugs that have a wide structural diversity and have shown a variety of biological activities. These compounds are produced in response to the harsh and competitive conditions that occur in the marine environment. Invertebrates are considered to be among the groups with the richest biodiversity. To date, a significant number of marine natural products (MNPs) have been established as antineoplastic drugs. This review gives an overview of MNPs, both in research or clinical stages, from diverse organisms that were reported as being active or potentially active in cancer treatment in the past seventeen years (from January 2000 until April 2017) and describes their putative mechanisms of action. The structural diversity of MNPs is also highlighted and compared with the small-molecule anticancer drugs in clinical use. In addition, this review examines the use of virtual screening for MNP-based drug discovery and reveals that classical approaches for the selection of drug candidates based on ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering may miss potential anticancer lead compounds. Finally, we introduce a novel and publically accessible chemical library of MNPs for virtual screening purposes.

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C−C and C−N Couplings in Reactions of the Benzylidyne-Bridged Complex [Mo2Cp2(μ-CPh)(μ-PCy2)(CO)2] with Small Unsaturated Organics

The ability of the title compound to promote C–C coupling processes has been analyzed by examining its reactions with diazoalkanes, alkynes, and other unsaturated organic molecules. The title compound reacted with N2CPh2 at room temperature to give a mixture of ketenyl complex [Mo2Cp2{μ-κ1:η2-C(Ph)CO}(μ-PCy2)(CO)(κ1-N2CPh2)] and carbyne complex [Mo2Cp2(μ-CPh)(μ-PCy2)(CO)(κ1-N2CPh2)], products which can be converted into each other by addition/removal of CO, respectively. In contrast, denitrogenation took place rapidly in analogous reactions with diazomethane and benzylazide at room temperature, to yield, respectively, the corresponding alkenyl [Mo2Cp2{μ-κ1:η2-C(Ph)CH2}(μ-PCy2)(CO)2] and iminoacyl [Mo2Cp2{μ-C(Ph)NCH2Ph}(μ-PCy2)(CO)2] derivatives, following from selective C–C and C–N couplings. The title compound reacted at 333 K with methyl propiolate to give the corresponding propenylylidene derivative [Mo2Cp2{μ-κ2:η3-CPhCHC(CO2Me)}(μ-PCy2)(CO)2], as a result of selective coupling of the carbyne ligand to the terminal carbon of the alkyne. A related complex could be obtained when using the internal alkyne dimethyl acetylenedicarboxylate.

Fuente de la publicación: 
  • Esther García, Daniel García-Vivó, Sonia Menéndez, and Miguel A. Ruiz. C–C and C–N Couplings in Reactions of the Benzylidyne-Bridged Complex [Mo2Cp2(μ-CPh)(μ-PCy2)(CO)2] with Small Unsaturated Organics. Organometallics 2016 35 (20), 3498-3506 DOI: 10.1021/acs.organomet.6b00552

Looking for inhibitors of the dengue virus NS5 RNA-dependent RNA-polymerase using a molecular docking approach

The dengue virus (DENV) nonstructural protein 5 (NS5) contains both an N-terminal methyltransferase domain and a C-terminal RNA-dependent RNA polymerase domain. Polymerase activity is responsible for viral RNA synthesis by a de novo initiation mechanism and represents an attractive target for antiviral therapy. The incidence of DENV has grown rapidly and it is now estimated that half of the human population is at risk of becoming infected with this virus. Despite this, there are no effective drugs to treat DENV infections. The present in silico study aimed at finding new inhibitors of the NS5 RNA-dependent RNA polymerase of the four serotypes of DENV. We used a chemical library comprising 372,792 nonnucleotide compounds (around 325,319 natural compounds) to perform molecular docking experiments against a binding site of the RNA template tunnel of the virus polymerase. Compounds with high negative free energy variation (ΔG <-10.5 kcal/mol) were selected as putative inhibitors. Additional filters for favorable druggability and good absorption, distribution, metabolism, excretion, and toxicity were applied. Finally, after the screening process was completed, we identified 39 compounds as lead DENV polymerase inhibitor candidates. Potentially, these compounds could act as efficient DENV polymerase inhibitors in vitro and in vivo.

Los miembros de la familia Flaviviridae causan una gran variedad de enfermedades en seres humanos y otras especies animales. Los  Flavivirus pueden transmitirse de los animales a los humanos por especies de vectores artrópodos tales como garrapatas y mosquitos. La familia Flaviviridae incluye cuatro géneros principales, Flavivirus, Pestivirus, Hepacivirus, y Pegivirus, así como algunos no clasificados viruses. El género Flavivirus  tiene un total de 67 virus, varios de los cuales infectan a los humanos, por ejemplo, el virus del dengue (DENV), el virus de la encefalitis japonesa, el virus de la fiebre amarilla, el virus del Nilo Occidental. El virus del dengue supone un grave riesgo para la salud humana, por ejemplo en 2013, causó  de 40 a 58 millones de infecciones sintomáticas, incluyendo 13.586 casos mortales. Sin embargo, a pesar de su enorme impacto en la salud pública en todo el mundo, las terapias antivirales eficaces contra DENV y otros flavivirus no se han desarrollado todavía.

La incidencia de DENV ha crecido rápidamente y ahora se estima que la mitad de la población humana está en riesgo de infectarse con este virus. A pesar de esto, no hay medicamentos eficaces para el tratamiento de infecciones de DENV. El presente estudio está dirigido a la búsqueda de nuevos inhibidores de la ARN polimerasa dependiente de ARN NS5 de los cuatro serotipos de DENV. Se utilizó una biblioteca química que comprende 372,792 compuestos no nucleótidos (alrededor de 325,319 compuestos naturales) para llevar a cabo experimentos de acoplamiento molecular contra un sitio de unión del túnel plantilla de ARN del virus de la polimerasa. Los compuestos con la variación de energía libre negativa alta (ΔG<-10,5 kcal / mol) fueron seleccionados como los inhibidores putativos. Se aplicaron filtros adicionales para una farmacobilidad favorable y buena absorción, distribución, metabolismo, excreción y toxicidad. Finalmente, después se completó el proceso de selección y se identificaron 39 compuestos como candidatos a inhibidores de la polimerasa. Potencialmente, estos compuestos podrían actuar como inhibidores de la polimerasa DENV como eficaces in vitro e in vivo.  Por otro lado, los investigadores de la UMH han creado la web para consultar los datos primarios de los experimentos de acoplamiento moleculares todas las  diferentes proteínas y bibliotecas químicas evaluadas. 

De este modo, de un total de más 325.000 compuestos, se han seleccionado 39 compuestos que se proponen para ser evaluados in vitro e in vivo reduciendo a un 0,012% el número de compuestos interesantes. Estos trabajos de modelado que han permitido evaluar el alto número de compuestos han sido realizados en el supercomputador LUSITANIA II. A partir de este trabajo,  se abre el camino a otros investigadores,  y se expone un conjunto muy limitado de compuestos para ser evaluados in vivo e in vitro y que permitan acercar y posibilitar la creación de una vacuna del virus Dengue. 

Fuente de la publicación: 
  • Vicente Galiano, Pablo Garcia-Valtanen, Vicente Micol, Jose Antonio Encinar. Looking for inhibitors of the dengue virus NS 5 RNA-dependent RNA-polymerase using a molecular docking approach. Drug Design, Development and Therapy. Volume 2016:10 Pages 3163-3181. DOI:

Structural essentials for β-N-acetylhexosaminidase inhibition by amides of prolines, pipecolic and azetidine carboxylic acids

This paper explores the computer modelling aided design and synthesis of β-N-acetylhexosaminidase inhibitors along with their applicability to human disease treatment through biological evaluation in both an enzymatic and cellular setting. We investigated the importance of individual stereocenters, variations in structure–activity relationships along with factors influencing cell penetration. To achieve these goals we modified nitrogen heterocycles in terms of ring size, side chains present and ring nitrogen derivatization. By reducing the inhibitor interactions with the active site down to the essentials we were able to determine that besides the established 2S,3R trans-relationship, the presence and stereochemistry of the CH2OH side chain is of crucial importance for activity. In terms of cellular penetration, N-butyl side chains favour cellar uptake, while hydroxy- and carboxy-group bearing sidechains on the ring nitrogen retarded cellular penetration. Furthermore we show an early proof of principle study that β-N-acetylhexosaminidase inhibitors can be applicable to use in a potential anti-invasive anti-cancer strategy.

Fuente de la publicación: 

Extending τ-Lop to model concurrent MPI communications in multicore clusters

Achieving optimal performance of MPI applications on current multi-core architectures, composed of multiple shared communication channels and deep memory hierarchies, is not trivial. Formal analysis using parallel performance models allows one to depict the underlying behavior of the algorithms and their communication complexities, with the aims of estimating their cost and improving their performance.

LogGP model was initially conceived to predict the cost of algorithms in mono-processor clusters based on point-to-point transmissions with network latency and bandwidth based parameters. It remains as the representative model, with multiple extensions for handling high performance networks, covering particular contention cases, channels hierarchies or protocol costs. These very specific branches lead LogGP to partially lose its initial abstract modeling purpose.

More recent lognP represents a point-to-point transmission as a sequence of implicit transfers or data movements. Nevertheless, similar to LogGP, it models an algorithm in a parallel architecture as a sequence of message transmissions, an approach inefficient to model algorithms more advanced than simple tree-based one, as we will show in this work.

In this paper, ττ–Lop model is extended to multi-core clusters and compared to previous models. It demonstrates the ability to predict the cost of advanced algorithms and mechanisms used by mainstream MPI implementations, such as MPICH or Open MPI, with high accuracy. ττ–Lop is based on the concept of concurrent transfers, and applies it to meaningfully represent the behavior of parallel algorithms in complex platforms with hierarchical shared communication channels, taking into account the effects of contention and deployment of processes on the processors. In addition, an exhaustive and reproducible methodology for measuring the parameters of the model is described.


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